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Funcionalización C-H transanular de los ácidos carboxílicos de cicloalcanos

Guowei Kang¹, Daniel A Strassfeld¹, Tao Sheng¹

¹Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.

|May 31, 2023

Resumen

Los nuevos ligandos permiten la arilación directa C-H de los cicloalcanes, facilitando la síntesis de moléculas cíclicas complejas. Este avance ofrece una ruta más eficiente a los carbociclos funcionales, cruciales para los productos farmacéuticos y naturales.

Área de la Ciencia:

Química orgánica
Química medicinal
Catálisis

Sus antecedentes:

Las moléculas orgánicas cíclicas prevalecen en los productos farmacéuticos, ofreciendo control sobre la forma molecular, la biodisponibilidad y la especificidad.
El desarrollo de métodos eficientes para sintetizar carbociclos funcionalizados es crucial para el descubrimiento y desarrollo de fármacos.
La funcionalización de C-H selectiva del sitio de los cicloalcanos presenta desafíos debido a la tensión del anillo durante la paladación transanular de C-H.

Objetivo del estudio:

Desarrollar nuevos ligandos para permitir la funcionalización directa de C-H selectiva del sitio de los carbociclos saturados.
Para lograr la arilación C-H transanular de ácidos carboxílicos cicloalcanos de pequeño a mediano tamaño.
Demostrar la utilidad del método desarrollado en la síntesis de moléculas biológicamente activas.

Principales métodos:

Síntesis y aplicación de dos clases de nuevos ligandos: las quinuclidinas-piridonas (L1, L2) y las sulfonamidas-piridonas (L3).
El uso de estrategias de activación C-H para la arilación directa de ácidos carboxílicos cicloalcanos.
Investigación de la regioselectividad de la funcionalización C-H en varios tamaños de anillo (ciclobutano a ciclooctano).

Principales resultados:

Los ligandos desarrollados permitieron con éxito la arilación transanular de γ-metileno C-H de los cicloalcanos.
Se logró una excelente γ-regioselectividad, incluso en presencia de múltiples enlaces β-C-H.
El protocolo facilitó las síntesis formales en dos pasos de moléculas pequeñas complejas y biológicamente activas patentadas, reduciendo significativamente los pasos sintéticos.

Conclusiones:

Este trabajo introduce un nuevo y poderoso método para la edición molecular de carbociclos saturados a través de la activación de C-H.
Los sistemas de ligandos desarrollados superan los desafíos anteriores en la funcionalización C-H selectiva del sitio de los sistemas cíclicos tensados.
Este avance proporciona una ruta sintética más eficiente y directa a valiosos andamios carbocíclicos para la química medicinal.

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